CN106573066A - Treprostinil formulations - Google Patents

Treprostinil formulations Download PDF

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Publication number
CN106573066A
CN106573066A CN201580043205.0A CN201580043205A CN106573066A CN 106573066 A CN106573066 A CN 106573066A CN 201580043205 A CN201580043205 A CN 201580043205A CN 106573066 A CN106573066 A CN 106573066A
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resin
exchange resin
preparation
compositionss
preparations
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K·帕利斯
C·张
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United Therapeutics Corp
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United Therapeutics Corp
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

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Abstract

Provided are ion complexes comprising treprostinil and an ion-exchange resin, pharmaceutical formulations based on such complexes, and methods of treating diseases and conditions using the ion complexes and pharmaceutical formulations.

Description

UT-15 preparation
Related application
This application claims the priority of the U.S. Provisional Patent Application 62/011,689 submitted to on 06 13rd, 2014, passes through Quote and include the full text of this application herein.
Field
It relates to having prostacyclin (prostacyclin) derivant such as UT-15 (treprostinil) ion-exchange resin complexes.
General introduction
A kind of embodiment is a kind of compositionss, and it includes a) UT-15 or derivatives thereof and b) anion exchange tree Fat, it is preferably in the form of ionic complex.
Another embodiment is pharmaceutical preparation, its include the ionic complex of this UT-15 or derivatives thereof with And pharmaceutically acceptable carrier.
Another embodiment is the method for preparing UT-15 preparation, and methods described includes mixture iron exchange resin And the solution containing UT-15 or derivatives thereof is forming suspension, the suspension comprising UT-15 or its spread out The ionic complex of biological and ion exchange resin.UT-15/ion exchange resin preferably forms resonating body (resonate) release of UT-15 during, it is coated to slow down course of dissolution with function coating.The resonating body of coating Suspension can be prepared into, for final dosage form.
Accompanying drawing
Fig. 1 shows the UV absorption spectrums of UT-15 glycol amine (diolamine), and has marked UT-15 two Optical density (OD) (OD) of the ethanolamine at 228nm (2.563) and 270nm (0.757) place.Spectrogrph produces number as initial data According to, the collection of illustrative plates of blank correction is then produced, correct solvent.Averaged spectrum is the meansigma methodss with two kinds of collection of illustrative plates of blank correction.Make Concentration is calculated with average collection of illustrative plates.
Fig. 2A-B show optical density (OD) and UT-15 concentration of the UT-15 at 228nm (A) and 270nm (B) place Function.
Fig. 3 is displayed in and the PUROLITE before UT-15 glycol amine complexationTMAnd DUOLITE (A)TM(B) resin Optical photograph.
Fig. 4 is displayed in UT-15 glycol amine：Resin ratio is 1:Under 1 (w/w) by UT-15 glycol amine with PUROLITETMDuring mixed with resin, the concentration of unconjugated UT-15 glycol amine and the function of time.
Fig. 5 A show i) UT-15 glycol amine load/gram PUROLITETMResin and ii) in PUROLITETMResin With the UT-15 glycol amine load efficiency in UT-15 complexation process.Fig. 5 B are PUROLITETMAnd UT-15 The optical photograph of complex.
Fig. 6 A show i) UT-15 load/gram DUOLITETMResin and ii) in DUOLITETMResin and Qu Qianlie UT-15 glycol amine load efficiency in ring element complexation process.Fig. 6 B are DUOLITETMWith the light of UT-15 complex Learn photo.
Specifically describe
Unless otherwise stated, " one " or " one kind " refer to/kind or multiple/kind.
The description of UT-15 is referring to U.S. Patent number 4,306,075.UT-15 and other prostacyclins spread out Biology can be found in following documents to prepare：Moriarty etc., J.Org.Chem.2004,69,1890-1902,《Future drugs (Drug of the Future)》, 2001,26 (4), 364-374, U.S. Patent number 6,441,245,6,528,688,6,700, 025,6,809,223,6,756,117,8,461,393,8,481,782,8,242,305,8,497,393,8,748,657, and 8,940,930, U.S. Patent Application Publication No. 2012/0190888 and 2012/0197041, and PCT Publication WO2012/ 009816。
The various applications of UT-15 and form see, for example, U.S. Patent number 5,153,222,5,234,953,6, 521,212,6,756,033,6,803,386,7,199,157,6,054,486,7,417,070,7,384,978,7,879, 909,8,563,614,8,252,839,8,536,363,8,410,169,8,232,316,8,609,728,8,350,079,8, 349,892,7,999,007,8,658,694,8,653,137,8,747,897, and 8,969,409, U.S. Patent Application Publication Number 2005/0165111,2009/0036465,2008/0200449,2010/0076083,2012/0216801,2008/ 0280986,2009/0124697,2013/0261187,2014/0275262,2014/0275 616, and 2014/0288314, with And PCT Application Publication WO00/57701.
The present invention relates to anion exchange resin and UT-15 and its complex of derivant.
And OrenitramTMAll comprising UT-15 as active component, and Ratified for treating pulmonary hypertension (PAH) by food and drug administration.UT-15 is injected Thing by hypodermically or vein injecting.UT-15 inhalation solution is come by using the suction of nebulizer Injection.The release tablet that UT-15 extends is oral.
The chemical name of UT-15 be 2- ((1R, 2R, 3aS, 9aS) -2- hydroxyl -1- ((S) -3- hydroxyl octyl groups) -2,3, 3a, 4,9,9a- hexahydro -1H- rings penta [b] naphthalene -5- base oxygen) acetic acid, and with following structures:
It is bent in UT-15 carboxylate moieties in the solution that pH value is 2 pH units of more than UT-15 pKa Prostacyclin has net negative charge.This negative charge can be used to form ionic complex with anion exchange resin.
Can also be by the UT-15 derivant with carboxylate moieties with the ionic complex of anion exchange resin To be formed.This UT-15 derivant can be one or more UT-15 ester, such as in U.S. Patent number 7,417, Those disclosed in 070, the content of the UT-15 ester of this article is totally incorporated herein by reference.UT-15 derivant may be used also For " Pegylation " UT-15, the UT-15 of Polyethylene Glycol is attached to, such as in PCT Publication WO00/ 57701 and U.S. Patent Application Publication No. 2014/0288314 in the Pegylation UT-15 form that discloses, the above is each The content of the UT-15 form of text is totally incorporated herein by reference.Unless otherwise stated, it is as used herein, " Qu Qianlie rings Element " is included before free acid UT-15, the pharmaceutically acceptable salt of UT-15, UT-15 derivant and song The pharmaceutically acceptable salt of row ring element derivant.
In some embodiments, UT-15 derivant can be the pharmaceutically acceptable salt of UT-15." medicine Acceptable salt on " refers to that salt is pharmaceutically acceptable, and with required pharmaceutical active.Pharmaceutically acceptable salt can be The pharmaceutically acceptable organic or inorganic alkali salt of UT-15.Representative pharmaceutically acceptable salt includes such as alkali metal Salt, alkali salt, ammonium salt.Pharmaceutically acceptable salt may include alkali addition (base addition) salt.UT-15 Base addition salts can be with sodium, ammonia, potassium, calcium, barium, lithium, magnesium, caesium, ethanolamine, diethanolamine, N- methyl glucose osamines, trometamol (tromethamine), choline, 1B, L-Arginine etc. are forming.The description of the salt of UT-15 see, for example, U.S. State's patent No. 7,417,070 and U.S. Patent Application No. 2014/0275616, the content of the UT-15 salt of each text of the above is led to Cross reference to include herein.
As used herein, term " UT-15-ion-exchange resin complexes " refers to the ion by following formation Complex：A) UT-15, the pharmaceutically acceptable salt of UT-15, UT-15 derivant and UT-15 At least one in the pharmaceutically acceptable salt of derivant and b) ion exchange resin, such as anion exchange resin.
Various resin anion (R.A.)s can be used to form complex with UT-15 derivant.Suitable ion exchange resin can For water miscible, and the organic and/or inorganic matrix containing functional group is may include, it is ion or under the conditions of appropriate pH Can be ionized.Ion exchange resin can be pharmaceutical inert.Organic substrate can be (for example, acrylic acid, the metering system of synthesis Acid, sulfonated phenylethylene, the polymer of sulfonation diethylbenzene or copolymer), or partial synthesis (for example, modified cellulose and Glucosan).Inorganic matrix may include with the modified silica gel of the addition of ionic group.For resin anion (R.A.), covalently connect The ionic group for connecing can be alkaline (for example, quaternary ammonium, such as trimethyl ammonium group, poly- (acryloyl amine-n-propyl group front three Base ammonium chloride (poly- APTAC), or poly- [(3- (Methacrylamide)-propyl group] trimethylammonium chloride (poly- MAPTAC)).It is cloudy Ion exchange resin can also be weakly alkaline (for example, primary amine, secondary amine and/or tertiary amine group, including polyvinylamine (polyethylene amine)).The pharmaceutical applications of ion exchange resin see, for example, Pande S.V., M.D.Kshirsagar, and A.V.Chandewar,《International journal (the International Journal of Advances in of the feasible progress of medicine Pharmaceutical Sciences)》2.2.1(2011):8-16.In general, it is adaptable to ion exchange chromatography and for example Ion exchanger type such as the deionization application of water is applied to the controlled release of pharmaceutical preparation.This ion exchanger Description see, for example, H.F.Walton, " ion exchange principle (Principles of Ion Exchange) " (pp:312-343) And " the technology and application (Techniques and Applications of Ion-Exchange of ion exchange chromatography Chromatography)”(pp:344-361),《Chromatograph (Chromatography)》. (E.Heftmann, editor), van Nostrand Reinhold companies, New York (1975). the ion exchange resin that can be used can have about 6 milliequivalents (meq)/gram Preferably 5.5meq/ gram or lower exchange capacity.In some embodiments, ion exchange resin have 5meq/ gram or Lower, 4.5meq/ gram or lower, 4meq/ gram or lower, 3.5meq/ gram or lower or 3meq/ gram or lower exchange appearance Amount.In some embodiments, ion exchange resin has 0.5meq/ gram -4meq/ gram, 1.0meq/ gram -3meq/ gram, 1.5meq/ gram -2.5meq/ gram, or 1.8meq/ gram -2.2meq/ gram of exchange capacity.
Generally, the size of ion-exchange resin particles is about 5 microns-about 1000 microns.In some embodiments, ion The size of exchanger resin granule can be about 10 microns-about 750 microns, and 20 microns -500 microns, 50 microns -400 microns, 50 is micro- - 200 microns of rice, and 75 microns -125 microns.In some embodiments, to can be about 100 micro- for the size of ion exchange resin Rice.In one embodiment, the granule used in liquid dosage form can be micro- about 40 microns-about 250 for liquid dosage form Within the scope of rice.In some embodiments, the granule for being used with solid dosage composition (such as tablet and capsule) can be 1000 microns less.The particle size of substantially less than lower limit is difficult to be processed in all steps of processing.Generally, it is uncoated Medicine ion exchanger resin granule can tend to the low side point in these scopes, and the medicine ion exchanger resin granule for coating can Tend to the high end points in these scopes.However, uncoated and coating medicine ion exchanger resin granule may be provided at this Within a little size ranges.
Regular shape can be used as resin with erose granule.The granule of regular shape is substantially conforming to several Those granules of what shape, such as spherical, oval, cylindrical etc..Erose granule is to be not considered as regular shape All granules, for example the granule with amorphous shape and because surface channel or deformation and there is the surface area of increase Granule.
A kind of example of anion exchange resin is cholestyramine (cholestyramine) resin, and it is a kind of type of highly basic 1 Anion exchange resin powder and with polystyrene substrate and quaternary ammonium functional group.Tradable anion is typically chloride, Its commutative another kind of anionic species is replaced by another kind of anionic species.A kind of commercially available resin cholestyramine is PUROLITETMA430MR resins.As described in its manufacturer Purolite, this resin has the average typical case less than 150 microns Granularity, the pH in 4-6 scopes, and 1.8-2.2meq/ are dried the exchange capacity of gram (gm).Another kind of pharmaceutical grade resin cholestyramine Can be used as DUOLITETMAP143/1094 is purchased from ROHM AND HAAS (Rohm and Haas) company.DUOLITETM AP143/1094 It is described as with following granularities by manufacturer：95% is less than 100 microns, and 40% is less than 50 microns.DUOLITETM AP143/ 1094 are also described as the pH with 4.0-6.0 (slurry numerical value) by manufacturer, the chloride content of 13.0%-14.0%, and Sodium glycollate (sodium glycholate) exchange capacity of 1.8-2.2meq/ dryings gram.From the confession of these and other resin Answer commercially available document (the PUROLITE A-430MR incorporated herein by reference of business；DOW cholestyramine USP, form numbering 177- 01877-204, Dow Chemical；DUOLITE AP143/1083, Rhom and Hass, IE-566EDS-February 06).
In some embodiments, anion exchange resin can be polyamine group resin.For example, in some embodiments, The polyamine group using acrylic acid or for example poly- amino acryl amides (polyaminoacrylamide) of polyacrylic acid substrate can be used Resin.A kind of example of polyamine group resin is PUROLITETM A830EMR。
In some embodiments, anion exchange resin can be bile acid chelating agent or resin.Bile acid chelating agent Example includes cholestyramine (trade mark Questran, Questran Light, Cholybar, Olestyr), colestipol (colestipol) (trade mark Colestid, Cholestabyl), examines and carrys out polyvinyl (colesevelam) (in European conduct Cholestagel sells, and sells as Welchol in the U.S.).The description of bile acid chelating agent see, for example, U.S. Patent number 4, 093,657,4,185,088,4,593,073,5,091,175,5,491,397,5,607,669,5,679,717,5,693, 675,5,917,007,5,919,832,5,929,184,6,066,678,6,129,910,6,190,649,6,203,785,6, 271,264,6,294,163,6,433,026,6,517,825,6,610,283,6,784,254,7,101,916,7,125, 547, and 7,229,613 and U.S. Patent Application Publication No. 2004/0151687,2007/0098678,2007/0122375, 2007/0190021,2008/0261942,2010/0179235,2011/0152204,2013/0022570, and 2013/ 189215。
In some embodiments, the compositionss comprising UT-15 and ion exchange resin can be made by following It is standby：Mixture iron exchange resin such as resin cholestyramine and UT-15 (such as UT-15 it is pharmaceutically acceptable Salt) solution such as aqueous solution, with formed comprising ion exchange resin and UT-15 or derivatives thereof ion network The suspension or dispersion of compound.Similarly, in some embodiments, the group comprising UT-15 and ion exchange resin Compound can be prepared by following：The solution example of mixing UT-15 (pharmaceutically acceptable salt of such as UT-15) Such as aqueous solution and ion-exchange resins such as resin cholestyramine, to be formed UT-15 or derivatives thereof and ion are included The suspension or dispersion of the ionic complex of exchanger resin.This suspension subsequently can be stirred, mixes or otherwise stirred Mix at least 15 minutes, at least 30 minutes, at least 45 minutes, at least 60 minutes, at least 75 minutes, at least 90 minutes, at least 120 points Clock, at least 150 minutes, at least 180 minutes, at least 210 minutes, at least 240 minutes, at least 270 minutes, or at least 360 minutes. After stirring, mixing or otherwise stirring, gained suspension or dispersion are may filter that.Be separated by filtration resonating body with it is any Free UT-15, leaves behind the resonating body as solid.Filter pore size can be as small as about 1 micron diameter, because at the beginning of resin It it is about 100 microns with beginning.
Can realize for UT-15 being attached to ion exchange resin using the method well known to the art.It is cloudy from Sub-exchange resin can be used in Cl- or OH- forms.Therefore, for acidic drug such as UT-15 is (derivative including it Thing) can be as described below with the association reaction of anion exchange resin：A () resin (if being in Cl- forms) (is in plus medicine Salt form)；B () resin (if being in Cl- forms) adds medicine (as free acid)；C () resin (being in OH- forms) is added Medicine (is in salt form)；D () resin (being in OH- forms) adds medicine (as free acid).In addition to (d), it is all this A little reactions have ionic byproducts, and the anion produced when being reacted competes the bound site on resin with anionic drugs Point.When this often results in balance, low-level medicine will be dropped and be attached to ion exchange resin.For acidic drug, can pass through Reaction (d) is combined come the stoichiometry for realizing medicine and resin.For example, with reference to carrying out as interval or post process, such as this Well known to technical field.
Preferably, the drug-ion exchange resin complex of such formation is collected by filtering, and with appropriate solvent Wash to remove unconjugated medicine or by-product.Complex can at room temperature or at elevated temperatures or under vacuo, It is air-dried in disk, in fluidized bed dryer, in microwave or in other suitable exsiccators.
In some embodiments for preparing complex, there is unique when medicine such as UT-15 load is entered During the ion exchange resin of particle size, using intermittent balance.Total ion exchange capacity represents what is measured under preferable experiment condition For ionic-exchange cationic or the maximum of the attainable capacity of anion.When by drug loading to ion exchange resin The capacity of Shi Shixian will be affected by for example following factors, and such as ion exchange resin is to the intrinsic selectivity of medicine, negative The concentration of load drug in solution and the also concentration of the competing ions present in loading solution.Speed under load will be by following shadows Ring：Medicine activity and medicine molecular dimension and in loading process polymer phase swelling reached degree.
When using interval or balance method by drug loading to ion exchange resin, it may be desirable to will be as many as possible Drug loading on ion exchange resin.In single equilibrium stage, unlikely fully from loading solution diversion medicaments. Therefore, it may be desirable to balance to realize reaching the required load on ion exchange resin more than once.Although entering from terminal stage Capable liquid phase loss medicine, from liquid phase separation resin between the stage, is realized medicine using two or more load stages Reach the mode of the maximum load on ion exchange resin.
In terms of the weight of UT-15-ion-exchange resin particles, the Qu Qianlie on ion exchange resin can be loaded to Within the scope of the amount of ring element can be for 1%-75% or 2%-70% or 3%-60% or 5%-50% or 10%-40% or these Subrange.Load is the amount of the amount/resin of UT-15, and the amount of UT-15 load can be before the song of such as 1.6g Row ring element/gram resin.
In some embodiments, ion exchange resin can be resin cholestyramine, such as DUOLITETMOr PUROLITETM Resin, and UT-15 (weight of UT-15 is based on UT-15 rather than its derivant of dissociating) and dry resin Weight ratio can be 1:10 to 10:1 or 1:5 to 5:1 or 1:3 to 3:1 or 1:2.5 to 2.5:1 or 1:2 to 2:1 or 1:1.8 arrive 1.8:1 or 1:1.6 to 1.6:1 or 1:1.5 to 1.5:1 or 1:1.4 to 1.4:1 or 1:1.3 to 1.3:1 or 1:1.2 to 1.2:1 or 1:1.1 to 1.1:1 or subrange or numerical value within the scope of these.
In some embodiments of suspension preparation, UT-15/ion-exchange resin complexes can be with following sides Formula is preparing：When disperse in aqueous suspension medium for it is oral when, UT-15 concentration will be 0.1-20mg/ml, 0.2- 15mg/ml, 0.5-10mg/ml, or about 1mg/ml-about 5mg/ml.
In some embodiments, ion exchange resin can be resin cholestyramine, such as DUOLITETMOr PUROLITETM Resin, and UT-15/ion-exchange resin complexes can be prepared in the following manner：It is bent when disperseing in an aqueous medium The concentration of prostacyclin is 0.1-100mg/ml either 0.2-90mg/ml either 0.3-80mg/ml or 0.5mg/ml-70mg/ Ml scopes either within 1mg/ml-50mg/ml or these subranges.
In some embodiments, UT-15-ion-exchange resin complexes can be processed by using release blocker, Further to extend or be modified from the drug release of UT-15-amberlite oil/fat composition.Release blocker can be wrapped Include the combination of insoluble polymer or insoluble polymer.
In some embodiments, discharge blocker and do not form only on UT-15-ion-exchange resin complexes Vertical layer, but formed substrate.The example of suitable release blocker includes such as polyvinyl acetate polymer or bag Polymeric blends (for example, KOLLICOAT SR 30D) containing it, cellulose acetate, ECN7NF acrylic Polymer or copolymer (e.g., the EUDRAGIT families of representational acrylic resin), phthalate, cellulose, or this water The combination of insoluble polymer or polymer system, these are all term used herein " release blocker ".These blocker Can further extend or change UT-15 from the release of UT-15-ion-exchange resin complexes, and maximization is obtained Obtain required release profile.Additionally, in some cases, it is capable of achieving to reduce obtaining prolongation drug release using release blocker The amount of the coating thickness needed for (it can be such as up to 24 hours).These blocker can make in a substantially pure form With, or use as the commercial preparation obtained from supplier.The use of release blocker see, for example, U.S. Patent number 8, 597,684。
In some embodiments, UT-15-ion-exchange resin complexes may include coating.In other words, exist In some embodiments, the granule of UT-15-ion-exchange resin complexes can be coated.In some embodiments In, this coating can be water-insoluble coating.In other embodiments, coating can for polymer coating (that is, including a kind of or The coating of multiple polymers), preferably insoluble polymer coating is (that is, including one or more insoluble polymer Coating).The example that can be used for the polymer of coating includes but is not limited to polyvinyl acetate, cellulose acetate, ethyl cellulose Polymer (such as Surerelease), phthalate, cellulose, hypromellose, ethyl acrylate, methyl methacrylate Copolymer, acrylic acid, methacrylic acid copolymer, ethoxyethyl methacrylates, methacrylic acid cyanoethyl ester, polypropylene Acid, polymethylacrylic acid, methacrylic acid alkylamide copolymer, polymethyl methacrylate, polymethacrylates, poly- third Acrylamide, aminoalkyl methyl acrylate copolymer, polymethacrylic acid anhydride, methyl propenoic acid glycidyl base ester copolymer, Polyvinyl acetate, polyvinylpyrrolidone and polystyrene.In some embodiments, can use includes cellulose acetate Coating.
The method for preparing and applying polymer coating is well known to the art.In some embodiments, can lead to Cross and spray the solution comprising coated polymer or suspension on UT-15/ion-exchange resin complexes to deposit bag Clothing.In this spraying process, UT-15/ion-exchange resin complexes can be suspended in fluid bed, for example Wurster Post.
In some embodiments, by weight, coatings can be uncoated UT-15-ion exchange resin network 0.5%-200%, 1%-150%, 1.5%-100%, 2.0%-75%, 2.5-50%, the 3%-30% of compound, or these Within the scope of subrange.In some embodiments, in addition to one or more insoluble polymer, coating can also be wrapped Include plasticizer.Plasticizer can promote the uniform coating of UT-15-ion-exchange resin complexes and/or strengthen to stop coating The tensile strength of layer.Suitable plasticizer is water miscible and water-insoluble.The example of suitable plasticizer includes such as last of the ten Heavenly stems Adipate, Propylene Glycol, Polyethylene Glycol, polyvinyl alcohol, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate Tributyl, citric acid tributyl, glyceryl triacetate, Soluphor P, and its mixture.The description of other plasticizers is referring to United States Patent (USP) The A1 of application publication number 2003/0099711.
When coating includes cellulose acetate polymer, the amount of this polymer can be by weight final coating 10%-99%, 30%-95%, 40%-90%, 50-90% or the subrange within the scope of these.
Design-adjustable is the song of the coating of oral digestion pharmaceutical composition (such as liquid suspension, tablet, caplet etc.) The rate of release of prostacyclin-ion-exchange resin complexes, with the drug release point needed for providing in following time periods Cloth：1-36 hours, -30 hours 2 hours, -24 hours 2 hours, 4-24 hours, 6-24 hours, 8-24 hours, or these scopes it Interior subrange.
This programmable rate of release mainly can control-(1) polymerization by least one in following two variables The thickness of thing coating and (2) are as described above, using release blocker component, it is added to UT-15-ion exchange resin Then complex carries out polymeric film coating step forming fine grained substrate.
By following UT-15-ion-exchange resin complexes can be used to treat the state of an illness, wherein known Qu Qianlie Ring element is useful：The compositionss comprising UT-15-ion exchange ionic complex of therapeutically effective amount have been given to be needed The object wanted, such as mankind.This state of an illness includes pulmonary hypertension, peripheral vascular disease, including intermittent claudication, ischemic Pathological changes, serious limb ischemia, diabetic neuropathic ulcer of foot, renal failure.In one embodiment, before will be comprising song The compositionss of row ring element-ion exchange ionic complex inject patient to treat pulmonary hypertension, including with NYHA classes II-IV The patient of PAH diseases and with WHO function class II-III diseases and the etiologic etiological patients of PAH.
UT-15-ion-exchange resin complexes can easily according to well known to the art method, use Pharmaceutically acceptable excipient is preparing.In some embodiments, preparation can only comprising uncoated UT-15-from Sub-exchange resin complex (that is, UT-15-ion-exchange resin complexes of this preparation not comprising coating).At some In embodiment, (that is, this preparation does not include UT-15-ion-exchange resin complexes that preparation can be only comprising coating Uncoated UT-15-ion-exchange resin complexes).Again in some embodiments, preparation can include the sum of coating The mixture of uncoated UT-15-ion-exchange resin complexes.In this mixture preparation, coating and be not coated with Part by weight alterable between the UT-15-ion-exchange resin complexes for covering.In some embodiments, coating And the part by weight between uncoated UT-15-ion-exchange resin complexes can be 100:1 to 1:100,50:1 arrives 1:50,20:1 to 1:20,10:1 to 1:10,5:1 to 1:5,2:1 to 1:2, or any subrange within the scope of these.
UT-15-ion-exchange resin complexes can be manufactured for being delivered by suitable path, including oral Ground, partly, intraperitoneal, endermically, the intramuscular in Sublingual, rectally, transbuccally, intranasal, liposome ground, by inhale Enter, vagina ground, ophthalmic ground, by local delivery (for example, by conduit or support), subcutaneous injection, fat, it is intraarticular, quiet Arteries and veins is injected or intrathecal.
The UT-15 being prepared-amberlite oil/fat composition can be stored and used or using conventional for follow-up Pharmaceutically acceptable carrier is prepared in time, with prepare for orally, nasogastric tube or convey otherwise it is final Digestible compositionss.For example, compositionss can have a form of liquid preparation such as suspension, or solid preparation, such as capsule, Tablet, buccal tablet (sublingual), powder, chip, bar, gel are including liquid gel etc..In one embodiment, tablet system Cause the tablet of oral.This oral solvent tablet can the disintegrate in less than about 60 seconds in mouth.
In some embodiments, UT-15-amberlite oil/fat composition may be produced that solid dosage formss, such as medicine Ball, tablet, capsule, caplet or powder.In some embodiments, UT-15-ion exchange resin formulations may be produced that Oral liquid dosage forms, such as solution, syrup, suspension, elixir, concentrate, emulsion or dispersion.
Can be prepared using acceptable carrier in conventional pharmaceutical or excipient and well known technology UT-15- Amberlite oil/fat composition.Although being not intended to be limited to theory, this conventional carrier or adsorbent include diluent, binding agent and Binding agent (such as cellulose derivative and acrylic acid derivative), lubricant are (such as magnesium stearate or calcium stearate or vegetable oil, poly- second Allyl diglycol, Talcum, sodium lauryl sulphate, polyoxyethylene monostearate), thickening agent, solubilizing agent, wetting agent, disintegrating agent, Coloring agent, flavouring agent, stabilizer, sweeting agent and various materials such as buffer agent and adsorbent, to prepare specific medicine Compositions.Stabilizer may include preservative and antioxidant, and other components, and this is for those of ordinary skill in the art Speech is obvious.
Suitable thickening agent includes the low alkyl of such as tragacanth, xanthan gum, bentonite, starch, Acacia farnesiana Willd. and cellulose Ether (including the hydroxyl and carboxy derivatives of cellulose ether).The example of cellulose includes such as hydroxypropyl cellulose, hydroxypropyl first Base cellulose, sodium carboxymethyl cellulose, Microcrystalline Cellulose (MCC) and the MCC with sodium carboxy methyl cellulose.A kind of real In applying mode, using tragacanth, and its amount for including is weight % of the about 0.1- about 1.0/volume (w/v) of compositionss and more excellent The about 0.5%w/v of selection of land compositionss.In another embodiment, using xanthan gum, in an amount of from about 0.025-about 0.5%w/v And preferably about 0.25%w/v.
UT-15-amberlite oil/fat composition may include moisturization composition give the bigger viscosity of liquid and Stability.Can be used for the suitable wetting agent of final preparation includes glycerol, Polyethylene Glycol, Propylene Glycol and its mixture.
The liquid oral compositions of the present invention may also include one or more surfactant, in an amount of from the highest of total preparation Up to about 5.0%w/v and preferably about 0.02%w/v to about 3.0%w/v.For preparing the table of the final composition of the present invention Face activating agent is typically organic material, and it contributes to stable and dispersion of the composition in aqueous systems, for suitable uniform Compositionss.Preferably, for example poly- (oxygen ethylene) (20) Sorbitan of the glass or plastic containers of selection Alcohol monoleate and sorbitan monooleate.These are commercially available as TWEENS and SPANS, and with various structures and molecule Measure to manufacture.
Suitable polysorbate includes polysorbate20, polysorbate40, polysorbate80 and its mixture. Most preferably, using polysorbate80.Surface active agent composition can in total composition about 0.01-about 2.0%w/v, it is and excellent Selection of land can account for the 0.1%w/v of composition total weight.
The second emulsifier/surfactant that can be applied in combination with polysorbate can be used, it can be poloxamer (poloxamer) such as Poloxamer 407.Lutrol 127 has about 22 HLB (hydrophile/lipophile balance), and with trade mark Pluoronic-127 (BASF--NJ) sells.Both surfactants can in substantially equal amounts be used.For example, moor Cough up husky nurse 407 and polysorbate80 each can be used together with following levels：About the 0.02-about 4.0% of the gross weight of preparation w/v。
Aqueouss can be obtained by the way that UT-15-amberlite oil/fat composition is dispersed in suitable aqueous carrier Suspension, optionally adds suitable viscosity intensifier (for example, cellulose derivative, xanthan gum etc.).Can be by by above-mentioned group Compound is scattered in suitable non-aqueous base load agent to obtain non-aqueous suspensions, optionally adds suitable viscosity intensifier (for example, hydrogenated edible fats, aluminium state (aluminum state) etc.).Suitable non-aqueous supporting agent includes such as almond oil, flower Oil generation, soybean oil or soybean oil or fractionated vegetable oil, such as fractionated coconut oil.
The preservative that can be used is included but is not limited to：Sodium benzoate, potassium sorbate, edetate (also referred to as ethylenediamine tetraacetic Acetate, or EDTA, such as disodium edetate) and parabenses (for example, methyl parahydroxybenzoate, para hydroxybenzene Ethyl formate, propyl p-hydroxybenzoate or butyl p-hydroxybenzoate) and sorbic acid.Available preservative includes as above institute Some chelating agen stated and other chelating agen, such as nitrilotriacetic acid(NTA) (NTA), ethylenediaminetetraacetic acid (EDTA), ethoxy Ethylenediamine triacetic acid (HEDTA), diethylenetriamine valeric acid (DPTA), 1，2-diaminopropane tetraacethyl (1,2-PDTA), 1,3- Diaminopropanetetraacetic acid (1,3-PDTA), (EGTA), 1,10- is double for 2,2- ethylene dioxies double [ethylimino two (acetic acid)] (2- pyridylmethyls) 1,4,7,10- tetra- overlaps decane (BPTETA)；Ethylenediamine (EDAMINE), anti-form-1,2- diaminourea hexamethylenes Alkane-N, N, N', N'- tetraacethyl (CDTA)；Ethylenediamine-N, N'- diacetate (EDDA), phenazine methosulfate (phenazine methosulphate)(PMS)；The chloro- indophenols (DCPIP) of 2,6- bis-, double (carboxymethyls) two diazonium -18- crown-s 6 (CROWN), porphin (porphine), chlorophyll, dimercaptopropanol, BAL (2,3- dimercapto -1- propanol), citric acid, tartaric acid, fumaric acid, Fructus Mali pumilae Acid and their salt.Foregoing preservatives are exemplary, but every kind of preservative must be evaluated to guarantee in every kind of preparation The compatibility of preservative and effect.Method for assessing efficiency of the preservative in pharmaceutical preparation is well known to the art 's.Preferred preservative is p-Hydroxybenzoate (paraben) preservative, including methyl parahydroxybenzoate, para hydroxybenzene Ethyl formate, propyl p-hydroxybenzoate and butyl p-hydroxybenzoate.Methyl parahydroxybenzoate and P-hydroxybenzoic acid third Ester is most preferred.Preferably, there is methyl parahydroxybenzoate and propyl p-hydroxybenzoate simultaneously in preparation, and to hydroxyl The ratio of essence of Niobe and propyl p-hydroxybenzoate is about 2.5:1 to about 16:1, and be 9 in some embodiments:1.
Wherein using in the case of adjuvant sweeting agent, it is contemplated that including those sweeting agents well known to the art, Including natural and artificial sweeting agent.Therefore, other sweeting agents may be selected from following non-limiting list：Water-soluble sweetening agent such as list Sugar；Disaccharidase and polysaccharide such as xylose, glucose, mannose, galactose, ribose, high-fructose corn syrup, glucose, Fructose, sugarcane Sugar, white sugar (sugar), maltose, boiling starch or corn-syrup solids；And sugar alcohol, for example Sorbitol, xylitol, Mannitol and its mixture.
In general, basis is selected and become for the amount of the sweeting agent needed for particular liquid preparation by the amount of sweeting agent Change.When the edible easily sweeting agent of extraction, this amount is usually 0.001 to the about 90 weight %/body of final fluid composition Product.Water-soluble sweetening agent as above is preferably used with following amounts：The weights of about 5%- about 70% of final fluid composition Amount/volume, and the most preferably weight/volume of about 10%- about 50%.Conversely, artificial sweetener (for example, sucralose, acesulfame potassium K and dipeptide-based sweetener) used with following amounts：The about 0.005%- about 5.0% of final fluid composition and most preferably about The weight/volume of 0.01%- about 2.5%.This tittle generally needs to realize required sweetness level, with the wind realized from flavor oil Taste level is unrelated.
Suitable flavor material includes the individually natural and artificial perfume with mixing and Herba Menthae, such as Herba Menthae, menthol, people Work Rhizoma et radix valerianae, Cortex Cinnamomi, various fruit flavors, it is contemplated to quintessence oil (such as thymol, eucalyptol (eculyptol), Mentholum, water Poplar acid methyl ester) etc..The amount of flavor material used is typically hobby problem, and it is subject to such as fragrance type, single spice and institute Need the impact of intensity.Therefore, measure alterable to obtain required result in the final product.This change is in the common skill in this area Within the ability of art personnel, and without the need for excessively experiment.Flavor material is generally used with the amount changed depending on single spice, And can for example measure the volume of for about 0.01%- about 3% weight/final composition weight.
Available coloring agent includes pigment such as titanium dioxide, and it can be included with following amounts：Up to about 1% weight/ Volume, and preferably up to reach about 0.6% weight/volume.Additionally, coloring agent may include to be applied to food, medicine and cosmetics Using dyestuff, also referred to as D＆C and F.D.＆C. dyestuffs etc..The material for above-mentioned range of application for receiving is preferably water Dissolubility.Exemplary embodiment includes indigo, and also referred to as F.D.＆C. is blue No. 2, and it is the indigo stannum disulfonic acid of 5,5' Disodium salt.Similarly, the dyestuff of referred to as F.D.＆C. greens 1 includes kiton colors, and is 4- [the p- sulphonyl of 4-N- ethyls Benzylamino (sulfobenzylamino)) the refined methyl of diphenyl]-[1- (the p- sulfonium benzyls of N- ethyl-N- ) -2, (sulfoniumbenzyl) the sub- enamine (cyclohexadienimine) of -5- hexamethylenes two].All F.D.＆C. and D.＆ And its comprehensive description of corresponding chemical constitution can be found in C.《Kirk-Othmer encyclopedia of chemical technology》, volume 5, the 857-884 page, its content is incorporated herein by reference.
The suitable oil ＆ fat that can be used will including partially hydrogenated plant fat or Animal fat, such as Oleum Cocois, Palm-kernel oil, Adeps Bovis seu Bubali, Adeps Sus domestica etc..Relative to the product that can be eaten, these compositions are generally used with following amounts：Up to about 7.0 Weight %, and preferably up to up to the final products of about 3.5 weight %.
It is also possible to use wetting agent in the composition to promote to disperse any hydrophobic combination.Wetting agent in compositionss should be selected Concentration, to realize optimum dispersion of the composition within compositionss, and using the wetting agent of minimum usable concentration.Should be understood that The wetting agent of amount concentration can cause compositionss such as suspension to flocculate.Suitable experience well known within the skill of those ordinarily skilled Method determining appropriate wetting agent and concentration, to realize optimal dispersion and avoid flocculation.Suitable wetting agent is listed in the U.S. Pharmacopeia 29.
Embodiment as herein described further by following working Examples, is illustrated by way of not limiting.
Embodiment
Introduction
The liquid dosage form of the sustained release to develop UT-15 is studied, wherein controllable medicine (Qu Qianlie rings Element) rate of release.In this research, UT-15 and ion exchange resin (IER) are the network between resin cholestyramine Compound is characterized as the candidate of the sustained release forms for UT-15.
Material
The chemical structural formula of UT-15 glycol amine (UT-15C) and UT-15 (UT-15) is as follows:
In our current research, using following material：1) UT-15 glycol amine (UT-15C) batch of material numbering:D02D11017；2) PUROLITETMA430MR resin cholestyramines, batch of material numbering:2009Y/14/5, by Purolite SRL (Brasov, Rome Buddhist nun It is sub-) friendship offer；With 3) DUOLITETMAP143/1083 resin cholestyramine USP, batch of material numbering:A075DBL013, by Tao Shiization Company (Chauny, France) friendship is provided.
Method
Using Fluostar Omega BMG Labtech UV spectrogrphs, about 0.1mg/mL is used from 220nm to 350nm UT-15 glycol amine aqueous solution carrying out UV absorptiometries, to determine λIt is maximum.Set up using the UT-15 of concentration known Two standard curves of 228nm and 270nm.Measure reaches the time of combination and unconjugated UT-15 and the balance of IER. 1 gram of resin is added to into the 10mg/mL UT-15 solution of 100mL.Stir 4 hours in suspension, and 30,60,90, 1 milliliter of sample is obtained at 120,180, and 240 minutes.Each sample is filtered by 0.45- μm of PTFE filter, and is passed through UV spectrographic method is determining the UT-15 concentration of resulting solution.Existed using the UT-15 and 1 gram of resin of concentration known 1:0.5,1:1,1:2, and 1:4, resin:Under the ratio of UT-15 (w/w), complexation experiment is carried out.Two kinds of trees are assessed respectively Fat, i.e. PUROLITETMAnd DUOLITETM.Complexation is calculated based on the difference between initial and final UT-15 concentration The amount of UT-15/gram resin.Percent load efficiency is calculated based on following formula：(1- [unconjugated Qu Qianlie rings Element]/[initial UT-15]) * 100.Using Leica DM IL LED lights microscopes and Leica DMC2900 microscopes Photographing unit, obtains the optical photograph of each resin before and after with UT-15 complexation.
As a result
Fig. 1-6 shows experimental result.Specifically, Fig. 1 show UT-15 diethanolamine UV absorb collection of illustrative plates, its There is maximum at 228nm and 270nm.Fig. 2A and 2B are shown for based on the Qu Qianlie in 228nm (2A) and 270nm (2B) place Ring element absorbs to determine the calibration curve of the concentration of unconjugated UT-15 (diethanolamine).Counted using 270nm curves Calculate all of concentration in complexation experiment.
Fig. 3 A and Fig. 3 B are respectively displayed on the PUROLITE before complexationTMAnd DUOLITETMThe optical photograph of resin.
The picture of Fig. 4 is displayed in 1:The UT-15 of 1 (w/w)：Resin ratio is by UT-15 and PUROLITETM During mixed with resin, the concentration of unconjugated UT-15 and the function of time.Fig. 4 shows before equilibrium is reached, is not associated with UT-15 concentration be remarkably decreased.
Around under environment and freezing environment, UT-15 diethanolamine is determined stable after 14 days.Also show song Prostacyclin diethanolamine is not bound with effect with 0.45- micrometer polytetrafluoroethylenes (PTFE) filter used in assessment.
The picture of Fig. 5 A shows i) UT-15 glycol amine load/gram resin and ii) in PUROLITETMResin and song UT-15 diethanolamine load efficiency in prostacyclin glycol amine complexation process.Fig. 5 B are PUROLITETMAnd Qu Qianlie The optical photograph of ring element glycol amine complex.
The picture of Fig. 6 A shows i) UT-15 load/gram resin and ii) in DUOLITETMResin and Qu Qianlie rings UT-15 load efficiency in plain complexation process.Fig. 6 B are DUOLITETMWith the optical photograph of UT-15 complex.
Conclusion
UT-15 has λ at the wavelength of 228nm and 270nmmax.UT-15 and resin cholestyramine formed from Sub- complex.After the stirring of 1 hour, reach combination and unconjugated UT-15 and resin balance.With song The concentration of prostacyclin diethanolamine increases, and more medicines are complexed to into resin, but the UT-15 for combining wherein Maximum is reached after 1.6g/g resins, initially enters plateau.Using lower concentration UT-15 diethanolamine when, Load is more effective, wherein most medicine is attached to resin.Preferred ratio for complexation can be 1:1, resin:Medicine Thing, wherein can be with reference to most medicine, with minimal amount of garbage.
Other documents
Pande S.V. etc.,《International journal (the International Journal of Advances of pharmaceutical science progress in Pharmaceutical Sciences)》2.2.1(2011):8-16. leaflets, the full content of this article is received by reference Enter herein.
*
Although specific embodiment is mentioned above, it should be understood that the present invention is not intended to be limited thereto.Ordinary skill Personnel should be understood that can carry out various variations to disclosed embodiment, and these variations should fall into the scope of the invention.

Claims (20)

1. a kind of compositionss, it includes a) UT-15 or UT-15 derivant, and b) anion exchange resin.
2. compositionss as claimed in claim 1, it is characterised in that UT-15 or UT-15 derivant and anion Exchanger resin forms ionic complex.
3. compositionss as claimed in claim 1, it is characterised in that the UT-15 is free acid.
4. compositionss as claimed in claim 1, it is characterised in that UT-15 is the pharmaceutically acceptable of UT-15 Salt.
5. compositionss as claimed in claim 1, it is characterised in that ion exchange resin includes bile acid chelating agent.
6. compositionss as claimed in claim 5, it is characterised in that bile acid chelating agent is selected from the group：Cholestyramine, examine and carry out polyvinyl And colestipol.
7. compositionss as claimed in claim 6, it is characterised in that ion exchange resin is resin cholestyramine.
8. compositionss as claimed in claim 7, it is characterised in that the weight ratio between UT-15 and resin cholestyramine is 1:2 to 2:1.
9. compositionss as claimed in claim 7, it is characterised in that it uses the aqueouss point of UT-15 and resin cholestyramine A prose style free from parallelism preparing, wherein the dispersion has the concentration of the UT-15 of 0.1mg/ml to 100mg/ml.
10. a kind of pharmaceutical preparation, it is included i) between UT-15 or UT-15 derivant and ion exchange resin The ionic complex of formation, and ii) pharmaceutically acceptable carrier.
11. preparations as claimed in claim 10, it is characterised in that the preparation is suspension.
12. preparations as claimed in claim 10, it is characterised in that the preparation is the solid dosage formss selected from tablet and capsule.
13. preparations as claimed in claim 10, it is characterised in that the preparation is the liquid dosage form for oral delivery.
14. preparations as claimed in claim 10, it is characterised in that the insoluble film bag of water being additionally included on the ionic complex Clothing.
15. preparations as claimed in claim 14, it is characterised in that the coating includes polymer.
16. preparations as claimed in claim 14, it is characterised in that the coating includes cellulose acetate.
17. preparations as claimed in claim 10, it is characterised in that the preparation also includes release blocker, and it is configured to prolong Release of the long or change from the UT-15 of the ionic complex.
18. preparations as claimed in claim 10, it is characterised in that the preparation is the preparation of controlled release, its offer is little 1 When time period of -36 hours on UT-15 controlled release.
A kind of 19. methods for treating pulmonary hypertension, it include by the preparation as claimed in claim 10 of therapeutically effective amount to Give object in need.
A kind of 20. methods for preparing UT-15 preparation, methods described includes：
Mixture iron exchange resin and the solution containing UT-15 or UT-15 derivant are described forming suspension Suspension includes the ionic complex of UT-15 or UT-15 derivant and ion exchange resin.
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